As patients are living longer with HIV infection, neurological complications such as dementia and peripheral neuropathy are becoming more prevalent and an important cause of morbidity in this population. To date, however, there is no effective treatment for these complications. Both the brain and the dorsal root ganglia show evidence of neurodegeneration while the virus replicates in glial cells or infiltrating monocytes. This suggests an important role for neuroprotective and neurotrophic modes of treatment for these conditions. This program project grant brings together researchers from several disciplines to closely interact with one another to develop new modes of treatment. During the duration of this program project we propose to conduct basic mechanistic in vitro studies using unique in vitro models for HIV dementia and peripheral neuropathy and to conduct animal studies as well as a phase 2 clinical trial. These projects will closely interact with a pharmaceutical company that has developed some novel immunophilin ligands that are highly potent neuroprotective and neurotrophic agents. We have taken a bench to bedside approach to evaluate their clinical use. A unique strength of this proposal is that it will identify compounds that are useful for treating both HIV dementia and peripheral neuropathy, since these conditions may coexist and occasionally may be difficult to differentiate. We have proposed five interactive projects and one core. Project l will determine the use of these agents in a human in vitro model for HIV dementia, Project 2 will similarly study the agents in the context of dorsal root ganglia neurons, Project 3 will determine subcellular mechanisms involved in neuroprotection. Project 4 will determine the use of a select compound in an SIV model of HIV dementia and peripheral neuropathy. Project 5 will conduct a phase 2 clinical trial of the compound identified as the lead candidate from the above projects. During the initial years of the Program project animal and clinical projects will develop and validate some novel tests that would serve as critical outcome measures during the trial. An administrative core will coordinate the interactions between all the projects and each of the researchers.